Airborne occupational exposures and risk of developing rheumatoid arthritis

Background: Rheumatoid Arthritis (RA) is an autoimmune, inflammatory disease with multifaceted aetiology. Cigarette smoke is the strongest environmental risk factor of RA, and research suggests that airborne exposures may trigger RA among genetically susceptible individuals. The aim of this thesis was to investigate the influence of airborne, occupational exposures on the risk of developing RA. The purpose of Study I was to explore whether there was any association between occupation and risk of developing RA. The airborne occupational exposures later studied were textile dust (Study II), asbestos and crystalline silica dust (Study III) and five types of organic dusts (Study IV). Methods: All four PhD projects are case-control studies. Study I is based on the Swedish Eipidemiological Investigation of Rheumatoid Arthritis (EIRA) study. In Study I we identified newly diagnosed RA cases from the age of 18 in the southern and central parts of Sweden from May 1996 until September 2014. 1-2 controls per case were randomly selected from the population register, matched on age, sex and residential area. Data on occupational titles and environmental risk factors were collected through an extensive questionnaire. Study II is based on the Malaysian EIRA (MyEIRA) study. We identified newly diagnosed female RA cases from 18 to 70 years of age from Peninsular Malaysia between August 2005 and December 2009. One control per case was selected and matched on age and residential area. Data on occupational titles and environmental risk factors were collected through an interview, based on an extensive questionnaire. In Study III and IV the study base comprised of men and women in Sweden from 1996 until 2013. RA patients were selected based on the information from EIRA, the national patient register, the Swedish Rheumatology Quality Register (SRQ) and the Swedish Prescribed Drug Register. Apart fom the EIRA controls, ten additional controls per case were randomly selected from the total population register. For Study III and IV the occupational titles were retrieved from the national Population and Housing censuses (1960-1990) and from Statistics Sweden’s LISA-register (2001-2010). We assessed the occupational exposure to the inorganic dusts asbestos, silica and five organic dusts by applying job-exposure matrices (JEMs) to the occupations of the participants. In all four studies, we calculated odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) by means of logistic regression analysis to assess the association between the main exposure and risk of RA. Results: Among men the production-related occupations bricklayers and concrete workers, electrical and electronics workers and material handling operators were associated with an increased risk of RA compared to workers within the professional, administrative and technical sectors after adjustment for potential confounding from cigarette pack-years, alcohol use, education and body mass index (BMI). Among women, we observed an increased risk of RA among assistant nurses and attendants. Men working with crystalline silica or asbestos had an increased risk of developing RA compared to unexposed workers. This finding may partly explain the increased risk among men working in production related occupations. The highest risk estimates for both asbestos and crystalline silica were observed among male workers with the longest duration of exposure, and for seropositive RA there was a significant dose-response trend for both agents. We could not detect an increased risk among women from asbestos or crystalline silica exposure. But fewer women than men had been working in occupations where they had been exposed to inorganic dusts and they also tended to have been exposed for a shorter period of time and to lower intensities. For the organic dusts wood, animal, paper, textile and flour, the risk estimates were more similar for men and women. Among these five types of dust, animal dust showed the most solid association with an increased risk of RA. The OR also increased with duration of exposure to animal dust. We observed an increased risk of RA among women from exposure to textile dust in Malaysia. There was also an interaction between textile dust exposure and HLA-DRB1 shared epitope (SE) alleles, predominantly for the risk of developing Anti- Citrullinated Protein/Peptide Antibody (ACPA) + RA. Also in the Swedish population there were signs of an association between textile dust and seropositive RA. Conclusions: This thesis demonstrates that your occupation may be associated with an increased risk of developing both seropositive and seronegative RA, where exposures to inorganic but also organic dusts play a role. Duration of exposure to organic and inorganic dusts is associated mainly with seropositive RA. These findings support the notion that the lung plays an important role in the pathogenesis of RA. The results can contribute to preventive measures at workplaces where workers are associated with an increased risk. This doctoral thesis highlights the importance to study inorganic and organic airborne exposures in countries with high or long-term exposure

La polémica Tugendhat-Habermas en torno a la cuestión de la identidad personal

La cuestión de la identidad personal ha sido muy discutida durante los últimos años. La atención puesta sobre este problema es una clara evidencia de la relevancia que tiene, entre otros, para el ámbito práctico en general. En este horizonte, Habermas y Tugendhat han sostenido una larga e interesante polémica sobre el concepto de identidad personal, polémica no siempre bien dimensionada. Esta querella ha servido para clarificar las diferentes variables que ingresan en esta problemática. En este trabajo analizaré críticamente cada una de las posturas con la finalidad de advertir el corazón argumental, buscar elementos en común y subrayar las insalvables diferencias.«Habermas-Tugendhat debate around the question of personal identity».The issue of personal identity has been much discussed in recent years. The attention given to this problem is clear evidence of the relevance that has, among others, the general practice area. In this perspective, Habermas and Tugendhat have maintained a long and interesting debate about the concept of personal identity, controversy is not always well measured. This lawsuit has served to clarify the different variables entering the problem. This paper critically analyze each of the positions in order to warn the heart of argument, seeking common and underscore the insuperable difference

Abiotic and biotic influence (pH, total nitrogen, insect biomass, and light intensity) on northern pitcher plant (Sarracenia purpurea) distribution at UMBS sites.

General EcologyIn contrast to the current knowledge about physiology and morphology of the northern pitcher plant, Sarracenia purpurea, very little is known about its habitat. In this study, we attempt to fill this knowledge gap by exploring the possibility of a significant relationship between S. purpurea fitness and abiotic and biotic factors including pH, light intensity, nitrogen content of groundwater and area-specific insect biomass. Measurements of the variables being studied were taken from two sites, Mud Lake Bog and Grass Bay Preserve, each located within 30 miles of UMBS. At each site, four arbitrary plots were chosen for a total of eight plots containing S. purpurea, at which we found a positive correlation between number of pitchers and diameter through a linear regression. This allowed us to use the diameter of each S. purpurea plant as a model for plant fitness. The mean number of pitchers for each site was determined to be significantly different by an independent t-test, but comparison of the dependent variable, diameter, with the independent variables, light intensity, pH, total nitrogen in groundwater, and area-specific insect biomass was insignificant. This study therefore accepts the null hypothesis; that there is not significant relationship between S. purpurea fitness and these abiotic and biotic factors.http://deepblue.lib.umich.edu/bitstream/2027.42/85763/1/Doktycz_Hillabrand_Yragui_Ilar_2011.pd

Direito internacional e direito internacional dos direitos humanos

O VIII Encontro Internacional do CONPEDI, ocorrido entre os dias 06 e 08 de setembro de 2018, na milenar, histórica e mui acolhedora Zaragoza (Espanha), ofereceu aos seus participantes conferências, painéis e grupos de trabalho de destacada qualidade, a exemplo o Grupo de Trabalho “Direito Internacional", que reuniu um qualificadíssimo grupo de pesquisadores de todas as regiões do Brasil, com trabalhos de pertinência acadêmica e grande relevância prática. Os artigos apresentados se destacaram pelo apuro intelectual, com discussões de sensível qualidade e sobre os mais variados temas do Direito Internacional na atualidade, com destaque para a América Latina, com o envolvimento dos alunos de mestrado e doutorado, professores e profissionais, a partir de discussões respeitosas e marcadas por uma perspectiva dialógica horizontal, democrática, aberta e plural. Um rico conjunto de temáticas, a demonstrar a contemporaneidade das discussões sobre o Direito Internacional na atualidade. Estamos honrados pela Coordenação desse relevante Grupo de Trabalho (GT), com o registro da satisfação em podermos debater com todos os autores e demais participantes. Por fim, registramos os cumprimentos ao CONPEDI, pela já costumeira qualidade dos encontros, e agradecemos aos colegas da Universidade de Zaragoza (Espanha) pela acolhida que tivemos na UNIZAR - nesse relevante momento de divulgação da pesquisa científica na área do Direito. Uma cultura, culinária, história milenar e hospitalidade que conquistaram a todos nós

How “Humane” Is Your Endpoint?—Refining the Science-Driven Approach for Termination of Animal Studies of Chronic Infection

Public concern on issues such as animal welfare or the scientific validity and clinical value of animal research is growing, resulting in increasing regulatory demands for animal research. Abiding to the most stringent animal welfare standards, while having scientific objectives as the main priority, is often challenging. To do so, endpoints of studies involving severe, progressive diseases need to be established considering how early in the disease process the scientific objectives can be achieved. We present here experimental studies of tuberculosis (TB) in mice as a case study for an analysis of present practice and a discussion of how more refined science-based endpoints can be developed. A considerable proportion of studies in this field involve lethal stages, and the establishment of earlier, reliable indicators of disease severity will have a significant impact on animal welfare. While there is an increasing interest from scientists and industry in moving research in this direction, this is still far from being reflected in actual practice. We argue that a major limiting factor is the absence of data on biomarkers that can be used as indicators of disease severity. We discuss the possibility of complementing the widely used weight loss with other relevant biomarkers and the need for validation of these parameters as endpoints. Promotion of ethical guidelines needs to be coupled with systematic research in order to develop humane endpoints beyond the present euthanasia of moribund animals. Such research, as we propose here for chronic infection, can show the way for the development and promotion of welfare policies in other fields of research. Research on chronic infection relies heavily on the use of animals, as only the integral animal body can model the full aspect of an infection. That animals are generally made to develop a disease in infection studies exacerbates the tension between human benefit and animal well-being, which characterizes all biomedical research with animals. Scientists typically justify animal research with reference to potential human benefits, but if accepting the assumption that human benefits can offset animal suffering, it still needs to be argued that the same benefits could not be achieved with less negative effects on animal welfare. Reducing the animal welfare problems associated with research (“refinement” [1]) is therefore crucial in order to render animal-based research less of an ethical problem and to assure public trust in research. Studies that are designed to measure time of death or survival percentages present a particularly challenging situation in which at least some of the animals are made to die from the disease. These studies are frequent in experimental research on severe infections. The scientific community, industry, and regulatory authorities have responded to the ethical concerns over studies in which animals die from severe disease by developing new policies and guidelines for the implementation of humane endpoints as a key refinement measure (e.g., [2]–[4]). The most widely used definition considers a humane endpoint to be the earliest indicator in an animal experiment of severe pain, severe distress, suffering, or impending death [5], underlining that ideally such indicators should be identified before the onset of the most severe effects. Euthanizing animals, rather than awaiting their “spontaneous” death, is important to avoid unnecessary suffering in studies in which data on survival is thought to be required for scientific or legal reasons. However, several questions remain open regarding how humane endpoints are to be applied to address real animal welfare problems. We used TB experiments in mice as a case study to highlight the potential to establish biomarkers of disease progress that can replace survival time as a measure of disease severity.Fundação para a Ciência e Tecnologia (SFRH/BD/38337/2007)

Gene expression profiling in the lung tissue of cynomolgus monkeys in response to repeated exposure to welding fumes

Many in the welding industry suffer from bronchitis, lung function changes, metal fume fever, and diseases related to respiratory damage. These phenomena are associated with welding fumes; however, the mechanism behind these findings remains to be elucidated. In this study, the lungs of cynomolgus monkeys were exposed to MMA-SS welding fumes for 229 days and allowed to recover for 153 days. After the exposure and recovery period, gene expression profiles were investigated using the Affymetrix GeneChip® Human U133 plus 2.0. In total, it was confirmed that 1,116 genes were up-or down-regulated (over 2-fold changes, P < 0.01) for the T1 (31.4 ± 2.8 mg/m3) and T2 (62.5 ± 2.7 mg/m3) dose groups. Differentially expressed genes in the exposure and recovery groups were analyzed, based on hierarchical clustering, and were imported into Ingenuity Pathways Analysis to analyze the biological and toxicological functions. Functional analysis identified genes involved in immunological disease in both groups. Additionally, differentially expressed genes in common between monkeys and rats following welding fume exposure were compared using microarray data, and the gene expression of selected genes was verified by real-time PCR. Genes such as CHI3L1, RARRES1, and CTSB were up-regulated and genes such as CYP26B1, ID4, and NRGN were down-regulated in both monkeys and rats following welding fume exposure. This is the first comprehensive gene expression profiling conducted for welding fume exposure in monkeys, and these expressed genes are expected to be useful in helping to understand transcriptional changes in monkey lungs after welding fume exposure

Functional analysis of frequently expressed Chinese rhesus macaque MHC class I molecules Mamu-A1*02601 and Mamu-B*08301 reveals HLA-A2 and HLA-A3 supertypic specificities

The Simian immunodeficiency virus (SIV)-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection and AIDS-related research, despite the potential that macaques of Chinese origin is a more relevant model. Ongoing efforts to further characterize the Chinese rhesus macaques’ major histocompatibility complex (MHC) for composition and function should facilitate greater utilization of the species. Previous studies have demonstrated that Chinese-origin M. mulatta (Mamu) class I alleles are more polymorphic than their Indian counterparts, perhaps inferring a model more representative of human MHC, human leukocyte antigen (HLA). Furthermore, the Chinese rhesus macaque class I allele Mamu-A1*02201, the most frequent allele thus far identified, has recently been characterized and shown to be an HLA-B7 supertype analog, the most frequent supertype in human populations. In this study, we have characterized two additional alleles expressed with high frequency in Chinese rhesus macaques, Mamu-A1*02601 and Mamu-B*08301. Upon the development of MHC–peptide-binding assays and definition of their associated motifs, we reveal that these Mamu alleles share peptide-binding characteristics with the HLA-A2 and HLA-A3 supertypes, respectively, the next most frequent human supertypes after HLA-B7. These data suggest that Chinese rhesus macaques may indeed be a more representative model of HLA gene diversity and function as compared to the species of Indian origin and therefore a better model for investigating human immune responses

The most common Chinese rhesus macaque MHC class I molecule shares peptide binding repertoire with the HLA-B7 supertype

Of the two rhesus macaque subspecies used for AIDS studies, the Simian immunodeficiency virus-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection, providing both insight into pathogenesis and a system for testing novel vaccines. Despite the Chinese rhesus macaque potentially being a more relevant model for AIDS outcomes than the Indian rhesus macaque, the Chinese-origin rhesus macaques have not been well-characterized for their major histocompatibility complex (MHC) composition and function, reducing their greater utilization. In this study, we characterized a total of 50 unique Chinese rhesus macaques from several varying origins for their entire MHC class I allele composition and identified a total of 58 unique complete MHC class I sequences. Only nine of the sequences had been associated with Indian rhesus macaques, and 28/58 (48.3%) of the sequences identified were novel. From all MHC alleles detected, we prioritized Mamu-A1*02201 for functional characterization based on its higher frequency of expression. Upon the development of MHC/peptide binding assays and definition of its associated motif, we revealed that this allele shares peptide binding characteristics with the HLA-B7 supertype, the most frequent supertype in human populations. These studies provide the first functional characterization of an MHC class I molecule in the context of Chinese rhesus macaques and the first instance of HLA-B7 analogy for rhesus macaques

The Influence of Behavioral, Social, and Environmental Factors on Reproducibility and Replicability in Aquatic Animal Models

The publication of reproducible, replicable, and translatable data in studies utilizing animal models is a scientific, practical, and ethical necessity. This requires careful planning and execution of experiments and accurate reporting of results. Recognition that numerous developmental, environmental, and test-related factors can affect experimental outcomes is essential for a quality study design. Factors commonly considered when designing studies utilizing aquatic animal species include strain, sex, or age of the animal; water quality; temperature; and acoustic and light conditions. However, in the aquatic environment, it is equally important to consider normal species behavior, group dynamics, stocking density, and environmental complexity, including tank design and structural enrichment. Here, we will outline normal species and social behavior of 2 commonly used aquatic species: zebrafish (Danio rerio) and Xenopus (X. laevis and X. tropicalis). We also provide examples as to how these behaviors and the complexity of the tank environment can influence research results and provide general recommendations to assist with improvement of reproducibility and replicability, particularly as it pertains to behavior and environmental complexity, when utilizing these popular aquatic models. © The Author(s) 2020. Published by Oxford University Press on behalf of the National Academies of Sciences, Engineering, and Medicine. All rights reserved.A.V.K. research was supported by the Russian Science Foundation grant 19-15-00053. He is the Chair of the International Zebrafish Neuroscience Research Consortium (ZNRC). This collaboration was supported, in part, through the NIH/NCI Cancer Center Support Grant P30 CA008748. The authors would like to thank Gregory Paull for sharing his photographs and insight into the natural habitat of zebrafish in Bangladesh